The invention relates to a method for hyperpolarizing nuclei contained in an MR (=magnetic resonance) agent using Brute Force, with the steps of
a) providing a sample, including the MR agent, optionally dissolved in a solvent, and a relaxation agent; and
b) exposing the sample to a magnetic field B0, with B0≧0.5 T, and a cryogenic temperature Tcr, with Tcr≦5K.
Such a method is known from WO 2009/004357 A2.
NMR (NMR: nuclear magnetic resonance) techniques, both in the field of spectroscopy (MRS: magnetic resonance spectroscopy) and imaging (MRI: magnetic resonance imaging), may be applied to gather information about a sample or sample area in a gentle, non-destructive way; in particular, clinical investigations on living patients can be done non-invasively. However, NMR techniques are generally limited by low signal intensities.
One way to increase signal intensities is to apply hyperpolarization techniques. Here, nuclei in a sample are prepared with a polarization level higher than corresponding to the Boltzmann distribution, and the hyperpolarized nuclei undergo an NMR experiment. In many NMR experiments, information about low γ/long T1 nuclei, respectively, are of particular interest, above all about 13C and 15N (γ: gyromagnetic ratio or gamma; T1: longitudinal relaxation time). Common methods are Dissolution Dynamic Nuclear Polarization (Dissolution DNP), Para-Hydrogen Induced Polarization (PHIP), and Brute Force Hyperpolarization (BFH).
Dissolution DNP (e.g. WO 1999/035508 Ardenkjaer-Larsen et al., WO 2002/037132-Ardenkjaer-Larsen et al.) has enjoyed relatively wide-spread acceptance by the commercial availability of dedicated equipment for hyperpolarization in the solid state followed by dissolution of the hyperpolarized sample. The method, however, has the draw-back that relatively complex instrumentation is required, including provisions for micro-wave irradiation of the solid sample, and that the sample must contain a polarizing agent, typically a free radical. For in vivo use of the dissolved sample the polarizing agent needs typically to be removed by chemical means. Moreover, unless the sample is continuously subjected to the conditions for hyperpolarization, the presence of the free radicals typically causes the enhanced polarization to be lost rapidly through relaxation and therefore the sample needs to be used immediately following the polarization process. In order to accelerate the preparation of hyperpolarized low γ/long T1 nuclei (such as 13C) here, it has been proposed to polarize 1H nuclei by DNP followed by a polarization transfer to the low γ nuclei such as 13C through the application of appropriate RF Cross Polarization pulses (e.g. S. Jannin et. al., Chem. Phys. Lett., 2011, 517, 234).
PHIP (e.g. WO1999/024080 Golman et al., WO 2008/155093 Duckett et al.) has not been accepted as broadly as Dissolution DNP mainly because the (catalytic) polarization transfer from para-hydrogen to the substrate molecule makes the method specific to certain classes of molecules. The catalyst is in general toxic and cannot be injected in vivo. Therefore the catalyst typically has to be removed in an additional step. Also, because the sample is in the liquid phase, thereby exhibiting liquid state T1 values which are typically relatively short, the polarization is lost through relaxation and the sample needs to be used immediately following the polarization transfer step.
In BFH (e.g. WO 2009/004357 Gadian, WO 2011/026103 Kalechofsy et al.) the nucleus of interest is polarized by generating very large thermal polarization at very low temperature and in a very strong magnetic field, followed by rapid heating of the sample. BFH is a rather general method; any substance can be polarized to very high degree of spin order corresponding to the Boltzmann distribution at a very high ratio of magnetic field strength and temperature. This spin order can in principle be maintained in the solid state for a relatively long time (many hours) at a moderately low temperature and modest magnetic field. There is no need for the addition of chemicals such as catalysts or free radicals and complex micro wave equipment is not required. Once the sample is brought to room temperature, a very high degree of Zeeman order is achieved resulting in the desired increase in NMR signal strength.
One disadvantage, however, of BFH is the long polarization build-up time, typically in the order of hundreds or thousands of hours. A potential mitigation of this problem is to make use of relaxation agents (also called acceleration agents) which allow for a faster build-up of the polarization. Care needs to be taken in the choice of the relaxation agent such as not to suffer rapid loss of polarization once the sample is brought into the liquid phase, though.
Kalechofsky et al. (WO 2011/026103) propose to make use of the specific temperature dependence of the relaxing effect of methyl rotors. This method allows rapid polarization build-up at low temperature and high magnetic field and the prolonged storage of the hyperpolarized material at intermediate field and temperature. The requirement to have methyl groups present in the substrate (MR agent), however, reduces the scope of the method to certain molecules. Kalechofsky et al. also propose to hyperpolarize the nuclei of interest indirectly by generating very large thermal 1H polarization at a very low temperature, followed by low field nuclear thermal mixing, transferring polarization to the nuclei of interest.
Gadian (WO 2009/004357) proposes the use of certain lanthanide complexes which have a favourable temperature/field dependence of their effectiveness as relaxation agent and can accelerate the polarization build-up rate by up to two orders of magnitude, from many days to hours. The lanthanide complexes, however, need to be either removed in the dissolution step, or used in their chelated form, to allow in vivo use.
It is the object of the invention to provide an improved Brute Force hyperpolarization method, which is broadly applicable and simple to perform.